Persistent, chronic human papillomavirus (HPV) infection is responsible for multiple diseases including recurrent respiratory papillomatosis (RRP) (usually caused by HPV 6 or 11); cervical intraepithelial neoplasia, cervical, penile and anal cancers (predominantly caused by HPV 16 or 18); and cancers of the oropharynx (HPV16). None of the immune studies of these diseases explain why only a subset of individuals infected with these ubiquitous HPVs fail to contain/eliminate their infection. Persistent active infection i the major risk factor for HPV-induced malignancy. We have extensively studied RRP, characterized by repeated growth of pre-malignant tumors that requires frequent surgeries that can cause mortality due to complete airway occlusion or cancer, and costs >100 million USD to treat/yr. We found that RRP patients have an HPV- specific TH2-like/Treg immunophenotype with a notable absence of TH17-like cells, and a failure to release the pro-inflammatory cytokine IL-36? robustly expressed by papillomas. RRP patients also constitutively, robustly express cyclooxygenase-2 (COX-2) in the airway that can bias immune responsiveness. Our preliminary data show that treatment with celecoxib, a COX-2 inhibitor, normalizes serum TH2-like chemokines in RRP, and causes long-term, sustainable clinical improvement; however, the mechanism is unknown. We focus on how this interventional strategy eliminates/contains persistent HPV infection and we test our novel hypothesis that rebalancing HPV-specific, Treg/TH17 adaptive immunity in RRP may eliminate/control persistent HPV infection. Specific Aims will test the hypothesis that a permissive, ineffective anti-HPV immune response can be reprogrammed through enhancement of the TH17/Treg balance in HPV persistently infected tissues, resulting in re-polarization of the adaptive response toward a TH1-like phenotype that can eliminate active disease. The aims are: 1) Determine whether IL-17 is required for release of IL-36? from HPV-infected laryngeal keratinocytes, and whether IL-36? can activate/mature Langerhans cells from RRP patients; 2) Determine if Tregs from RRP patients can be reprogrammed to become TH17-like T-cells through ligation of their aryl hydrocarbon (AHR) receptor; and 3) Determine if TH17-like T-cells induced by IL-36? activated LCs, or following ligation of their AHR, can become HPV-specific TH1-like T-cells that can support the generation of cytotoxic TC1-like T-cells. These studies will test the novel concept that remodulating pathogen-specific, immune responses of patients with persistent HPV infection simulate to function like most HPV-infected individuals who have latent HPV infection and show no signs of disease. Our unique ongoing clinical trial of celecoxib allows for a direct comparison of in vitro studies with in vivo responses and will provide a rationale to use this approach to treat other persistent HPV infections. These studies could also provide critical and urgently needed insight into why some patients infected with high risk HPVs of the genital tract and oropharynx ultimately develop malignancy.